I. Problem/Challenge.

In many patients presenting with critical illness, respiratory failure may be one feature of their physiologic disturbance. As a result, mechanical ventilation is a common component of management in the intensive care unit (ICU). Although mechanical ventilation provides needed physiologic support, it also places patients at risk for adverse events including agitation, delirium, infection, trauma, hemodynamic dysfunction and neuromuscular weakness. Above conditions may lead to distress and increased metabolic demand by increasing sympathetic tone and ventilator asynchrony.

It is critical to aim for early liberation and extubation of patients, when physiologically appropriate. Careful consideration of sedation and analgesia, in particular, dosing and duration are essential, which would be directed to the cause of discomfort and distress as much as possible. Additionally, avoidance of paralytic therapy, unless absolutely necessary, is preferred.

The major causes of ventilator asynchrony and restlessness in adult ICU patients are pain, agitation and delirium, and therefore initial drug choice should be based on underlining cause of distress.

II. Identify the Goal Behavior.

Sedation and Analgesia.

The best way to assure appropriate and effective use of sedation and analgesia is by using validated sedation and analgesia scales to systematically assess patient comfort while on mechanical ventilation. The most common sedation scale used in the ICU is the Richmond Agitation Sedation Scale (RASS), outlined below in section V. The Richmond Agitation-Sedation Scale (RASS) and Sedation-Agitation Scale (SAS) are the most valid and reliable sedation assessment tools for measuring quality and depth of sedation in adult ICU patients.

A commonly used pain scale is the Behavioral Pain Scale (BPS), also outlined below. The Behavioral Pain Scale (BPS) and the Critical-Care Pain Observation Tool (CPOT) are the most valid and reliable pain scales for monitoring pain in medical, postoperative, or trauma (except for brain injury) adult ICU patients who are unable to self-report and in whom motor function is intact and behaviors are observable.

These scales, or other similarly validated scales allow practitioners to accurately adjust medication therapy with the goal of minimizing the amount of sedation and analgesia required to achieve patient-ventilator synchrony and comfort.

The ideal sedative agent would be the one with shortest half life and least side effects. Choice of sedative is further narrowed based on cause of discomfort, vital signs and level of sedation desired and of course its availability in an institution.

Typically, practitioners will choose to use low doses of a combination of medications which act via different mechanisms, such as a benzodiazepine and an opioid. Ideally, bolus sedation and analgesia will be used rather than continuous infusions to minimize the effect of medication build up in the body of a critically ill patient whose metabolism may be adversely effected by their condition. If a continuous infusion is maintained, daily sedation interruption is necessary to assess underlying cortical function and to assure cognition remains intact, as well as minimizing critical illness acquired neuromuscular weakness.

Commonly used sedatives and analgesics are listed below. Try choosing the agent that addresses the cause of discomfort and use minimal dose possible. Intermittent administration is preferred above continuous infusion except for propofol and dexemdetomidine. If clinically possible and agitation not related to alcohol and benzodiazepine withdrawal, trial of non-benzodiazepines is recommended as it would be associated with less time spent on mechanical ventilation.

Narcotic analgesics:

Morphine

Hydromorphone

Fentanyl

Benzodiazepines:

Midazolam

Lorazepam

Diazepam

Propofol

Dexmedetomidine

Antipsychotics:

Haloperidol

Atypical antipsychotics (e.g. Quetiapine and Olanzapine)

A few tips to help choosing initial preferred agent:

Make sure medication side effect would not interfere with its use; e.g. in hypotensive patient, dexmedetomidine or propofol may drop blood pressure further.

Fentanyl is used frequently in ICU setting as has less effect on blood pressure, is faster acting and has shorter half life compared to morphine and hydromorphone.

Midazolam is short and faster acting than other 2 agents. When midazolam is used as infusion for less than 48-72 h, it still keeps its shorter half life but after about 48-72 h, its active metabolite will start accumulating causing more prolonged sedative effect. If still an infusion is required, switching to lorazepam is recommended.

Using high dose diazepam and lorazepam infusion may cause metabolic acidosis and nephrotoxicity related to their carrier (Propylene glycol).

Propofol is an ideal sedative in ICU if patient is hemodynamically stable as it is short acting with short half life which makes it preferred agent in neuro-ICUs for frequent neurological exam. High dose propofol may cause Propofol syndrome which is more seen in pediatric population than adults. Of note, urine may turn green when using propofol but it has no adverse clinical side effect. If used more than 72 h, need to follow triglyceride levels as its carrier contains lipids.

Dexmedetomidine is a newer agent which is an alpha 2 agonist with anxiolytic and sedative effects that causes less respiratory depression and can even be used even in non-intubated patients. Like clonidine it may cause hypotension and bradycardia.

Treatment for hyperactive delirium and agitation related to delirium is discussed in a different chapter.

Neuromuscular Blockade.

Standards are less clear cut for neuromuscular blocker (paralytic) therapy. There are no compelling evidence-based studies demonstrating either a benefit in survival or other secondary end points to recommend routine use of paralytics. However, in patients with respiratory physiologic disturbances refractory to maximal ventilator therapy, treatment with paralytics may be considered. Examples of potential indications for paralytic therapy include patient-ventilator dysynchrony, respiratory muscle contraction, elevated intracranial pressure, persistent impairments in gas exchange, and high total body oxygen consumption and use during certain procedures like intubation.

When using a paralytic in these and other situations, it is critical to make absolutely sure the patient is maximally sedated prior to initiation of therapy. This determination can be difficult. While there is no gold standard to determine the level of anesthesia in a critically ill patient, the use of a monitor that assesses level of anesthesia, such as the Bispectral Index (BIS) monitor, as an adjunct to clinical evaluation may be considered. Of note, while these instruments have been demonstrated to achieve adequate anesthesia in the OR setting, the literature is less compelling in the ICU setting. Reliance on bispectral index monitoring as the sole source of monitoring of level of sedation in paralyzed patients is not consistent with the current standard of care and could result in a false sense of security that the patient is adequately sedated. The appropriate degree of sedation prior to initiating paralytic therapy is typically based on clinical judgment rather than use of BIS monitor.

There are a variety of neuromuscular blocking agents each with different times of onset, duration of action and metabolism. The type of neuromuscular blocker (NMB) chosen is most often directed by the particular pharmacy formulary, though more than one may be available. There is no consensus in the literature as to which NMB to choose. However, the majority of NMBs are metabolized either by the liver or the kidney, making it important to pay attention to dosing. The exceptions to this rule are atracurium and its more potent isomer, cisatracurium, which are degraded by ester hydrolysis and Hoffman elimination, and therefore do not require dose adjustment.

Classes of Neuromuscular Blockers.

There are two major classes of neuromuscular blockers - depolarizing and non-depolarizing.

Depolarizing NMBs are acetylcholine (Ach) analogs and competitively bind Ach receptors at the neuromuscular junction, causing initial activation of the neuromuscular junction (NMJ) followed by blockade. The only depolarizing NMB available in the United States is succinylcholine, used primarily to facilitate intubation, but not for prolonged paralysis. Succinylcholine may cause and potentiate hyperkalemia and should be avoided in situations where hyperkalemia is expected.

Non-depolarizing NMBs are competitive antagonists of Ach and bind Ach receptors, thereby blocking function at the NMJ. Below is a list of several common non-depolarizing NMBs:

Pancuronium: Long acting.

Vecuronium: Intermediate acting.

Rocuronium: Intermediate acting with rapid onset.

Atracurium: Intermediate acting.

Cisatracurium: Isomer of atracurium. Also intermediate acting.

When using paralytics, it is standard of care to monitor the level of paralysis using a peripheral nerve stimulator. A peripheral nerve stimulator (electrode) is attached to a patient’s extremity. Current is provided to stimulate nerve conduction to generate a finger twitch, also known as a train-of-four (TOF). Prior to starting paralytics, a baseline measurement should be made to determine the amount of current necessary to generate the twitch. There can be anywhere from 0-4 twitches. The goal TOF for adequate neuromuscular blockade is typically 1/4 or 2/4.

Dexmedetomidine: Continuous infusion: Start with 0.2 mcg/kg/hour. Titrate every 30 minutes by 0.1-0.2 mcg/kg/hour. Usual maintenance dose is 0.2-0.7 mcg/kg/hour but also has been used as high as 1.2-1.5 mcg/kg/hour with or without bolus dosing. If side effects of bradycardia or hypotension occur, stop infusion for 15-30 minutes and may resume and re-challenge at half of the previous dose.

RASS should be measured q4h once patient achieves goal sedation, and with any change in condition.

BPS should be measured q4h once patient achieves goal analgesia, with any change in condition, and 30 minutes’ post administration of pain medication.

Step 2: Neuromuscular blockade.

Identify a need for neuromuscular blockade.

Ensure adequate level of sedation (most commonly determined by sedation scales with consideration for use of an instrument which measures degree of anesthesia).

See step 1 (above).

Bispectral Index (BIS) score: The BIS monitor produces a score that can range from 0-100 with 0 being equivalent to no electroencephalograph (EEG) activity and 100 being fully awake and alert. Typically, adjusting sedation to a score of 40-60 is sufficient to safely use paralytics.

Set a goal for paralysis.

Measure the train-of-four: The goal number of twitches for adequate neuromuscular blockade is typically 1/4 or 2/4.

Patients on neuromuscular blockers should NEVER have sedation/analgesia held until the neuromuscular blocker is stopped and paralysis has resolved.

Adjusting dosing for oversedation.

Bolus sedation: Hold sedation/analgesia until RASS at goal, then decrease medication doses by 50% or lengthen the interval between doses.

Continuous infusion: Hold drip until RASS at goal, then restart medication at 50% of prior rates or consider bolus dosing. For patients on narcotic or benzodiazepine sedative drips for more than a week, a daily 10-25% dose reduction is recommended to prevent withdrawal symptoms as soon as clinical situation permits and when patient is closer to liberation from mechanical ventilation.

Daily sedation awakening: Patients should undergo daily awakening from sedation/analgesia to assess cognitive function, as well as to assess whether they are ready for a Spontaneous Breathing Trial (SBT) on mechanical ventilation. See the module on mechanical ventilation for more details on liberation from ventilation.

IV. Common Pitfalls.

Sedation and Analgesia.

The most common sedation and analgesia pitfall in the ICU is oversedation. The tendency when intubating a patient is to sedate the patient to make them completely unresponsive, which is reasonable because it facilitates safe, efficient and successful institution of mechanical ventilation for critically ill patients. However, once intubated and stable on mechanical ventilation, it is important to reduce sedation to as minimal a level as the patient can comfortably tolerate and which achieves the intended goal of mechanical ventilation.

The importance of appropriately sedating a patient cannot be overstated. Failure to sufficiently sedate can result in patient discomfort, agitation, anxiety, hemodynamic instability and difficulty with patient-ventilator synchrony. However, oversedation can be equally damaging, with studies demonstrating a variety of complications including higher ventilator and ICU days, risk of deconditioning, increased rates of cognitive dysfunction, post traumatic stress disorder, and higher ventilator associated pneumonia rates.

Neuromuscular Blockade.

There are two major complications of NMB use in critically ill patients. The first is prolonged neuromuscular recovery time, defined as an increased duration of time before function recovers primarily due to active metabolites and/or hepatic/renal dysfunction.

The second complication of neuromuscular blockade is acute quadriplegic myopathy syndrome (AQMS) or critical illness acquired myopathy. AQMS can be difficult to distinguish from other ICU syndromes such as steroid and ICU myopathies and critical illness polyneuropathy. Patients with AQMS can present with diffuse weakness, motor deficits in all extremities, elevated creatinine phosphokinase (CPK) with histologic evidence of myonecrosis, and an abnormal electromyogram (EMG) demonstrating acute denervation.

The literature is inconsistent, but there is a suggestion that the combination of a neuromuscular blocker with a glucocorticoid is particularly detrimental, and can last weeks to months, often with incomplete restoration of muscle function.

Prevention of complications of paralysis.

Several preventive measures are suggested when utilizing a NMB in the ICU:

As noted above, a TOF should be measured to maintain appropriate level of paralysis.

Eyes should be taped shut or patients should receive lubricating drops or ointments to prevent corneal abrasions.

Patients should be repositioned regularly to reduce risk of skin breakdown and pressure sores.

All paralyzed patients should be maintained on deep venous thrombosis (DVT) prophylaxis unless there is a specific absolute contraindication.

Paralytic needs should be re-assessed every 12-24 hours to address the need for ongoing NMB.

Paralyzed patients should be seen and evaluated by physical therapy (PT) regularly to maintain mobility and reduce muscle atrophy.

BPS scale: 3 categories, each scored on a scale of 1-4. Observe patient for approximately 3 minutes for each item and assign a score of 1-4. Total scores from each category. Low score = 3; high score = 12. Typical goal BPS score is 4-5.

Murray, M, Cowen, J, DeBlock, H, Erstad, B, Gray, A, Tescher, A, McGee, W, Prielipp, R, Susla, G, Jacobi, J, Nasraway, S, Lumb, P. "Developed Through the Task Force of the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM), in collaboration with the American Society of Health-System Pharmacists (ASHP), and in alliance with the American College of Chest Physicians; and approved by the Board of Regents of ACCM and the Council of SCCM and ASHP Board of Directors: Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient". Crit Care Med.
vol. 30. 2002. pp. 141-156.

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